Macitentan

Macitentan, sold under the brand name Opsumit, is an endothelin receptor antagonist (ERA) developed by Actelion and approved for the treatment of pulmonary arterial hypertension (PAH).[3] The other two ERAs marketed as of 2014 are bosentan and ambrisentan.[3] Macitentan is a dual ERA, meaning that it acts as an antagonist of two endothelin (ET) receptor subtypes, ETA and ETB.[3] However, macitentan has a 50-fold increased selectivity for the ETA subtype compared to the ETB subtype.[4] The drug received approval from the U.S. Food and Drug Administration (FDA) on October 13, 2013.[5]

Macitentan
Clinical data
Trade namesOpsumit
Other namesACT-064992
AHFS/Drugs.comMonograph
MedlinePlusa615033
License data
Pregnancy
category
  • AU: X (High risk)
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
MetabolismHydrolysis, oxidation (CYP3A4)
Excretion2/3 urine, 1/3 faeces
Identifiers
  • N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N'-propylsulfamide
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC19H20Br2N6O4S
Molar mass588.28 g·mol−1
3D model (JSmol)
  • Brc1ccc(cc1)c3c(ncnc3OCCOc2ncc(Br)cn2)NS(=O)(=O)NCCC
  • InChI=1S/C19H20Br2N6O4S/c1-2-7-26-32(28,29)27-17-16(13-3-5-14(20)6-4-13)18(25-12-24-17)30-8-9-31-19-22-10-15(21)11-23-19/h3-6,10-12,26H,2,7-9H2,1H3,(H,24,25,27)
  • Key:JGCMEBMXRHSZKX-UHFFFAOYSA-N

Macitentan is available as a generic medication in the United States as of April 2021.[6]

Adverse effects

The FDA has issued a black box warning for macitentan for embryo-fetal toxicity. It is only available to females in the U.S through a risk evaluation and mitigation strategy (REMS) program.[7]

Mechanism of action

Endothelin and endothelin receptors

Endothelin (ET) is an extremely potent blood vessel constricting substance that is secreted by endothelial cells.[8] In the lungs, the most common ET form released is ET-1.[8] ET-1 release can occur through both constitutive and non-constitutive pathways.[8] Upon release, ET-1 can bind to the ET receptors that are expressed on arterial smooth muscle cells and fibroblasts in the lungs.[8] ET receptors are G protein coupled receptors and, when activated, lead to an increase in intracellular calcium levels via the Gαq signaling pathway.[8] There are two receptor subtypes that endothelin will bind to: ETA and ETB. ETA is associated with cell growth and vasoconstriction while ETB is responsible for anti-proliferation of cells, vasodilation and ET-1 clearance. The rise in intracellular calcium leads to contraction of the arterial smooth muscle, as well as vascular remodelling due to cell proliferation.[8] Prolonged constriction and fibrosis are factors in the pathogenesis of PAH.[3]

Role of macitentan

Macitentan blocks the ET1-dependent rise in intracellular calcium by inhibiting the binding of ET-1 to ET receptors. Blocking of the ETA receptor subtype seems to be of more importance in the treatment of PAH than blocking of ETB, likely because there are higher numbers of ETA receptors than ETB receptors in pulmonary arterial smooth muscle cells.[8] The blocking of Endothelin 1 leads to vasodilation and decreases the proliferation of cells in the vessels of the artries which contributes to the narrowing and leads to the pulmonary arterial hypertension.

Pharmacokinetics

Macitentan is taken as a 10 mg oral dose once a day.[3] Its half-life in humans is about 16 hours and steady state is reached by the third day of administration.[9] It is absorbed slowly into the plasma.[10] Macitentan dealkylates into the active metabolite ACT-132577, which reaches its peak plasma concentration about 30 hours after the first dose is administered, and has a half-life of approximately 48 hours.[10] Although ACT-132577 has a lower affinity for the ET receptors than its parent compound,[4] It maintains higher plasma concentrations than macitentan.[10] Both compounds can be excreted from the body through the urine or feces.[9]

Co-administration of ciclosporin has only a slight effect on the concentrations of macitentan and its active metabolite, while rifampicin decreases the area under the curve (AUC) of the drug's blood plasma concentration by 79%, and ketoconazole approximately doubles it. This corresponds to the finding that macitentan is mainly metabolised via the liver enzyme CYP3A4.[11]

ACT-132577, the active metabolite of macitentan

Experimental pharmacokinetics

Macitentan has slow association kinetics.[8] Its potency increases 6.3-fold when it is pre-incubated with pulmonary arterial smooth muscle cells for 120 minutes compared to 10 minutes with pulmonary arterial smooth muscle cells.[8] Macitentan also has a high receptor occupancy half-life (approximately 17 minutes) compared to bosentan (approximately 70 seconds) and ambrisentan (approximately 40 seconds).[8] This increased receptor occupancy half-life allows macitentan to act as a non-competitive antagonist of ET receptors.[8] Bosentan and ambrisentan are both competitive antagonists.[8]

References
  1. "Prescription medicines: registration of new chemical entities in Australia, 2014". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 10 April 2023.
  2. "Opsumit- macitentan tablet, film coated". DailyMed. 22 September 2020. Retrieved 24 October 2020.
  3. Hong IS, Coe HV, Catanzaro LM (April 2014). "Macitentan for the treatment of pulmonary arterial hypertension". The Annals of Pharmacotherapy. 48 (4): 538–47. doi:10.1177/1060028013518900. PMID 24458948. S2CID 24720486.
  4. Iglarz M, Binkert C, Morrison K, Fischli W, Gatfield J, Treiber A, et al. (December 2008). "Pharmacology of macitentan, an orally active tissue-targeting dual endothelin receptor antagonist". The Journal of Pharmacology and Experimental Therapeutics. 327 (3): 736–45. doi:10.1124/jpet.108.142976. PMID 18780830. S2CID 6315900.
  5. "Actelion receives us fda approval of Opsumit (macitentan) for the treatment of pulmonary arterial hypertension". Actelion. Archived from the original on 2013-10-23. Retrieved 22 October 2013.
  6. "Macitentan: FDA-Approved Drugs". U.S. Food and Drug Administration (FDA). Retrieved 19 June 2021.
  7. Opsumit [package insert] Whippany, NJ: Bayer HealthCare Pharmaceuticals 2017
  8. Gatfield J, Mueller Grandjean C, Sasse T, Clozel M, Nayler O (2012). "Slow receptor dissociation kinetics differentiate macitentan from other endothelin receptor antagonists in pulmonary arterial smooth muscle cells". PLOS ONE. 7 (10): e47662. Bibcode:2012PLoSO...747662G. doi:10.1371/journal.pone.0047662. PMC 3471877. PMID 23077657.
  9. Bruderer S, Hopfgartner G, Seiberling M, Wank J, Sidharta PN, Treiber A, Dingemanse J (September 2012). "Absorption, distribution, metabolism, and excretion of macitentan, a dual endothelin receptor antagonist, in humans". Xenobiotica; the Fate of Foreign Compounds in Biological Systems. 42 (9): 901–10. doi:10.3109/00498254.2012.664665. PMID 22458347. S2CID 38365884.
  10. Sidharta PN, van Giersbergen PL, Halabi A, Dingemanse J (October 2011). "Macitentan: entry-into-humans study with a new endothelin receptor antagonist". European Journal of Clinical Pharmacology. 67 (10): 977–84. doi:10.1007/s00228-011-1043-2. PMC 3169777. PMID 21541781.
  11. Bruderer S, Aänismaa P, Homery MC, Häusler S, Landskroner K, Sidharta PN, et al. (March 2012). "Effect of cyclosporine and rifampin on the pharmacokinetics of macitentan, a tissue-targeting dual endothelin receptor antagonist". The AAPS Journal. 14 (1): 68–78. doi:10.1208/s12248-011-9316-3. PMC 3282010. PMID 22189899.
  • "Macitentan". Drug Information Portal. U.S. National Library of Medicine.
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